There are no treatments of glioma multiforme that substantially extend life. The reasons behind the inability to effectively treat glioma remain obscure. In this proposal, based on robust preliminary data, we develop a novel hypothesis, that the enzyme, a disintegrin and metalloproteinase-17, also known as, tumor necrosis factor converting enzyme (ADAM17, TACE) fosters glioma invasion, proliferation and survival. Thereby inhibition of ADAM17 will be effective in reducing tumor growth. We propose three specific aims and corresponding hypotheses, directed at fully investigating the potential of ADAM17 as a pro tumorgenic agent and inhibition of ADAM17 as an anti-tumor treatment. Aim 1: Characterize the function of ADAM17 in glioma invasion, proliferation and survival in vitro, and in tumor progression in vivo. Hypothesis 1a: Increased ADAM17 activity induces invasion and promotes cell proliferation and survival of glioma cells in vitro and promotes tumor progression in vivo. Hypothesis 1b: ADAM17 activation of the epidermal growth factor (EGF) signaling pathway promotes glioma invasion, cell proliferation and survival, by stimulating the PI3K/Akt pathway. Aim 2: Investigate the role of ADAM17 in glioma progression in the context of hypoxic stress. Hypothesis 2: ADAM17 transcription and proteolytic activity are up-regulated by hypoxia-induced cellular stress, and this increase leads to enhanced glioma proliferation, invasiveness and survival. Aim 3: Investigate the therapeutic effectiveness of ADAM17-targeting RNAi gene therapy to treat U87 and HF66 human glioma xenographs in nude mouse models. Hypothesis 3: ADAM17-targeting RNAi gene therapy decreases ADAM17 expression and proteolytic activity within glioma cells, and thus reduces tumor progression and prolongs survival of nude mice bearing intracranial glioma xenographs. Both in vitro and in vivo models of glioma are employed in the proposed studies. Methods used range from siRNA to laser capture confocal microscopy and magnetic resonance imaging in an effort to dissect the contribution of ADAM17 to tumor progression and to elucidate the molecular bases for tumor progression and effective treatment. Our long term goal is to develop an effective treatment for this devastating brain tumor and to translate our findings from the experimental system to the human. PUBLIC HEALTH RELEVANCE: This project is designed to investigate the function of a disintegrin and metalloprotease-17 (ADAM17/TACE) proteolysis in glioblastoma multiforme tumor progression. The contribution of ADAM17 to tumor cell proliferation and invasion will be elucidated, with a special focus upon ADAM17 induction due to low glucose and oxygen availability. We will determine whether disruption or augmentation of ADAM17 activity lead to changes in tumor progression, and whether ADAM17-silencing gene therapy provides a therapeutic effect in a mouse model of human glioma.